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Journal of Lipid Research, Vol. 46, 1596-1603, August 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Histone deacetylase 1: a target of 9-hydroxystearic acid in the inhibition of cell growth in human colon cancer

Natalia Calonghi^1,*, Concettina Cappadone^*, Eleonora Pagnotta^*, Carla Boga, Carlo Bertucci, Jessica Fiori, Gianluca Tasco^**, Rita Casadio^** and Lanfranco Masotti^*

^* Department of Biochemistry G. Moruzzi, University of Bologna, Bologna, Italy
Department of Organic Chemistry A. Mangini, University of Bologna, Bologna, Italy
Department of Pharmaceutical Sciences, University of Bologna, Bologna, Italy
^** Centro Interdipartimentale per le Ricerche Biotecnologiche Laboratory of Biocomputing, University of Bologna, Bologna, Italy

Published, JLR Papers in Press, February 16, 2005. DOI 10.1194/jlr.M400424-JLR200

¹ To whom correspondence should be addressed. e-mail: natalia.calonghi{at}unibo.it

Recent studies have shown that an endogenous lipoperoxidation product, 9-hydroxystearic acid (9-HSA), acts in colon carcinoma cells (HT29) as a growth inhibitor by inducing p21^WAF1 in an immediate-early, p53-independent manner and that p21^WAF1 is required for 9-HSA-mediated growth arrest in HT29 cells. It is conceivable, therefore, to hypothesize that the cytostatic effect induced by this agent is at least partially associated with a molecular mechanism that involves histone deacetylase 1 (HDAC1) inhibition, as demonstrated for sodium butyrate and other specific inhibitors, such as trichostatin A and hydroxamic acids. Here, we show that, after administration, 9-HSA causes an accumulation of hyperacetylated histones and strongly inhibits the activity of HDAC1. The interaction of 9-HSA with the catalytic site of the enzyme has been highlighted by computational modeling of the human HDAC1, using its homolog from the hyperthermophilic Aquifex aeolicus as a template.

Consistent with the experimental data, we find that 9-HSA can bind to the active site of the protein, showing that the inhibition of the enzyme can be explained at the molecular level by the ligand-protein interaction.

Supplementary key words endogenous lipid peroxidation products • tumor • mass spectrometry • computational modeling

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